c-MYC—Making Liver Sick: Role of c-MYC in Hepatic Cell Function, Homeostasis and Disease

Over 35 years ago, c-MYC, a highly pleiotropic transcription factor that regulates hepatic cell function, was identified. In recent years, a considerable increment in the number of publications has significantly shifted the way that the c-MYC function is perceived. Overexpression of c-MYC alters a wide range of roles including cell proliferation, growth, metabolism, DNA replication, cell cycle progression, cell adhesion and differentiation. The purpose of this review is to broaden the understanding of the general functions of c-MYC, to focus on c-MYC-driven pathogenesis in the liver, explain its mode of action under basal conditions and during disease, and discuss efforts to target c-MYC as a plausible therapy for liver disease.

[1]  J. Whitfield,et al.  Tumor microenvironment: becoming sick of Myc , 2011, Cellular and Molecular Life Sciences.

[2]  J. Sanders,et al.  Postnatal liver growth and regeneration are independent of c-myc in a mouse model of conditional hepatic c-myc deletion , 2012, BMC Physiology.

[3]  J. Horton,et al.  Molecular mediators of hepatic steatosis and liver injury. , 2004, The Journal of clinical investigation.

[4]  H. Jansen,et al.  Oncogenes in retroviruses and cells: biochemistry and molecular genetics. , 1986, Advances in cancer research.

[5]  S. Friedman Molecular mechanisms of hepatic fibrosis and principles of therapy , 1997, Journal of Gastroenterology.

[6]  X. Guan,et al.  Prognostic significance of c‐myc and AIB1 amplification in hepatocellular carcinoma , 2002, Cancer.

[7]  Alex Mas,et al.  Overexpression of c‐myc in the liver prevents obesity and insulin resistance , 2003, FASEB journal : official publication of the Federation of American Societies for Experimental Biology.

[8]  F. Bosch,et al.  Evidence from transgenic mice that myc regulates hepatic glycolysis , 1995, FASEB journal : official publication of the Federation of American Societies for Experimental Biology.

[9]  Shelly C. Lu,et al.  Deregulated methionine adenosyltransferase α1, c‐Myc, and Maf proteins together promote cholangiocarcinoma growth in mice and humans‡ , 2016, Hepatology.

[10]  Stuart H. Orkin,et al.  A Myc Network Accounts for Similarities between Embryonic Stem and Cancer Cell Transcription Programs , 2010, Cell.

[11]  Shelly C. Lu,et al.  Switch from Mnt‐Max to Myc‐Max induces p53 and cyclin D1 expression and apoptosis during cholestasis in mouse and human hepatocytes , 2009, Hepatology.

[12]  M. Lindström,et al.  Myc and E2F1 induce p53 through p14ARF-independent mechanisms in human fibroblasts , 2003, Oncogene.

[13]  S. Thorgeirsson,et al.  Central role of c-Myc during malignant conversion in human hepatocarcinogenesis. , 2009, Cancer research.

[14]  R. Braren,et al.  c-myc in the hematopoietic lineage is crucial for its angiogenic function in the mouse embryo , 2008, Development.

[15]  C. Dang,et al.  Induction of ribosomal genes and hepatocyte hypertrophy by adenovirus-mediated expression of c-Myc in vivo. , 2000, Proceedings of the National Academy of Sciences of the United States of America.

[16]  M. Pickering,et al.  miR-17 and miR-20a temper an E2F1-induced G1 checkpoint to regulate cell cycle progression , 2009, Oncogene.

[17]  C. Robert Cloninger,et al.  Genetics of Alcoholism and Related End-Organ Damage , 1988, Seminars in liver disease.

[18]  L. Penn,et al.  Reflecting on 25 years with MYC , 2008, Nature Reviews Cancer.

[19]  S. Thorgeirsson,et al.  Transgenic mouse model for synergistic effects of nuclear oncogenes and growth factors in tumorigenesis: interaction of c-myc and transforming growth factor alpha in hepatic oncogenesis. , 1993, Cancer research.

[20]  N. Iizuka,et al.  Involvement of c-myc-regulated genes in hepatocellular carcinoma related to genotype-C hepatitis B virus , 2006, Journal of Cancer Research and Clinical Oncology.

[21]  John S Lazo,et al.  Improved low molecular weight Myc-Max inhibitors , 2007, Molecular Cancer Therapeutics.

[22]  S. Thorgeirsson,et al.  E2F1 blocks and c-Myc accelerates hepatic ploidy in transgenic mouse models. , 2003, Biochemical and biophysical research communications.

[23]  J. Radziuk,et al.  Hepatic glucose uptake, gluconeogenesis and the regulation of glycogen synthesis , 2001, Diabetes/metabolism research and reviews.

[24]  Michael Q. Zhang,et al.  A global transcriptional regulatory role for c-Myc in Burkitt's lymphoma cells , 2003, Proceedings of the National Academy of Sciences of the United States of America.

[25]  N. Thompson,et al.  Sequential protooncogene expression during rat liver regeneration. , 1986, Cancer research.

[26]  B. Edgar,et al.  Genomic binding by the Drosophila Myc, Max, Mad/Mnt transcription factor network. , 2003, Genes & development.

[27]  D. Felsher,et al.  Defective double-strand DNA break repair and chromosomal translocations by MYC overexpression , 2003, Proceedings of the National Academy of Sciences of the United States of America.

[28]  Chi V Dang,et al.  MYC on the Path to Cancer , 2012, Cell.

[29]  D. Felsher,et al.  Transient excess of MYC activity can elicit genomic instability and tumorigenesis. , 1999, Proceedings of the National Academy of Sciences of the United States of America.

[30]  M E Greenberg,et al.  Myc requires distinct E2F activities to induce S phase and apoptosis. , 2001, Molecular cell.

[31]  P. Borro,et al.  Alcohol and hepatocellular carcinoma: a review and a point of view. , 2014, World journal of gastroenterology.

[32]  G. Evan,et al.  Myc-Is this the oncogene from Hell? , 2002, Cancer cell.

[33]  R. Eils,et al.  Etiology‐dependent molecular mechanisms in human hepatocarcinogenesis , 2007, Hepatology.

[34]  S. Thorgeirsson,et al.  Transgenic Mouse Model for Synergistic Effects of Nuclear Oncogenes and Growth Factors in Tumorigenesis: Interaction of c-myc and Transforming Growth Factor α in Hepatic Oncogenesis , 1993 .

[35]  D. Felsher,et al.  Hepatotoxin-Induced Changes in the Adult Murine Liver Promote MYC-Induced Tumorigenesis , 2008, PloS one.

[36]  G. Kay,et al.  Autocrine mitogen IgEGF cooperates with c-myc or with the Hcs locus during hepatocarcinogenesis in transgenic mice. , 1995, Oncogene.

[37]  Y. Fukuda,et al.  Expression of oncogenes in human liver disease. , 2008, Liver.

[38]  A. Grinberg,et al.  Visualization of Myc/Max/Mad Family Dimers and the Competition for Dimerization in Living Cells , 2004, Molecular and Cellular Biology.

[39]  E. Prochownik,et al.  Efficacy, pharmacokinetics, tisssue distribution, and metabolism of the Myc–Max disruptor, 10058-F4 [Z,E]-5-[4-ethylbenzylidine]-2-thioxothiazolidin-4-one, in mice , 2009, Cancer Chemotherapy and Pharmacology.

[40]  K. Ko,et al.  A mouse model of cholestasis-associated cholangiocarcinoma and transcription factors involved in progression. , 2011, Gastroenterology.

[41]  T. Morgan,et al.  Alcohol and hepatocellular carcinoma. , 2004, Gastroenterology.

[42]  F. Tacke,et al.  Overexpression of c-myc in hepatocytes promotes activation of hepatic stellate cells and facilitates the onset of liver fibrosis. , 2013, Biochimica et biophysica acta.

[43]  N. Lydon,et al.  Electroporation of cultured adult rat hepatocytes with the c-myc gene potentiates DNA synthesis in response to epidermal growth factor. , 1988, Experimental cell research.

[44]  J. Pawlotsky,et al.  Hepatitis C virus-induced activation of β-catenin promotes c-Myc expression and a cascade of pro-carcinogenetic events , 2013, Oncogene.

[45]  P. Borro,et al.  Alcohol and gastrointestinal oncology. , 2010, World journal of gastrointestinal oncology.

[46]  Francesco Donato,et al.  Hepatocellular carcinoma in cirrhosis: incidence and risk factors. , 2004, Gastroenterology.

[47]  S. Thorgeirsson,et al.  Transgenic mouse models in carcinogenesis: interaction of c-myc with transforming growth factor alpha and hepatocyte growth factor in hepatocarcinogenesis. , 2003, British journal of clinical pharmacology.

[48]  C. Trautwein,et al.  Application of magnetic resonance imaging in transgenic and chemical mouse models of hepatocellular carcinoma , 2010, Molecular Cancer.

[49]  D. W. Goodwin Genetic influences in alcoholism. , 1987, Advances in internal medicine.

[50]  I. Weinstein Addiction to Oncogenes--the Achilles Heal of Cancer , 2002, Science.

[51]  P. Neiman,et al.  Genomic instability during Myc-induced lymphomagenesis in the bursa of Fabricius , 2006, Oncogene.

[52]  Kyoichi Inoue,et al.  Hypomethylation of the c-myc oncogene in liver cirrhosis and chronic hepatitis , 1989, Gastroenterologia Japonica.

[53]  N. Thompson,et al.  Proto-oncogene expression and growth factors during liver regeneration. , 1986, Symposium on Fundamental Cancer Research.

[54]  D. Calvisi,et al.  Distinct anti-oncogenic effect of various microRNAs in different mouse models of liver cancer , 2015, Oncotarget.

[55]  Vijay Kumar,et al.  Hepatocellular carcinoma in a hepatitis B ‘x’ transgenic mouse model: A sequential pathological evaluation , 2003, Journal of gastroenterology and hepatology.

[56]  E. Ziff,et al.  The nerve growth factor-responsive PC12 cell line does not express the Myc dimerization partner Max , 1995, Molecular and cellular biology.

[57]  L. Hurley,et al.  Targeting MYC Expression through G-Quadruplexes. , 2010, Genes & cancer.

[58]  C. Croce,et al.  Human c-myc onc gene is located on the region of chromosome 8 that is translocated in Burkitt lymphoma cells. , 1982, Proceedings of the National Academy of Sciences of the United States of America.

[59]  A. Bradley,et al.  A null c-myc mutation causes lethality before 10.5 days of gestation in homozygotes and reduced fertility in heterozygous female mice. , 1993, Genes & development.

[60]  G. Evan,et al.  Transcriptional activation by the human c-Myc oncoprotein in yeast requires interaction with Max , 1992, Nature.

[61]  Howard Y. Chang,et al.  MYC can induce DNA breaks in vivo and in vitro independent of reactive oxygen species. , 2006, Cancer research.

[62]  Zhiping Weng,et al.  Global mapping of c-Myc binding sites and target gene networks in human B cells , 2006, Proceedings of the National Academy of Sciences.

[63]  David E. Muench,et al.  c-Myc and Cancer Metabolism , 2012, Clinical Cancer Research.

[64]  E. Prochownik,et al.  MYC oncogenes and human neoplastic disease , 1999, Oncogene.

[65]  J. Sanders,et al.  Nucleolar localization of hepatic c-Myc: a potential mechanism for c-Myc regulation. , 2005, Biochimica et biophysica acta.

[66]  R. Palmiter,et al.  Oncogene-induced liver neoplasia in transgenic mice. , 1989, Oncogene.

[67]  Christopher H. Contag,et al.  MYC inactivation uncovers pluripotent differentiation and tumour dormancy in hepatocellular cancer , 2004, Nature.

[68]  C. Dang,et al.  Conditional deletion of c-myc does not impair liver regeneration. , 2006, Cancer research.

[69]  H. Hsu,et al.  Amplification of the c-myc gene in human hepatocellular carcinoma: biologic significance. , 1993, Journal of the Formosan Medical Association = Taiwan yi zhi.

[70]  S. Thorgeirsson,et al.  E2F1 inhibits c-Myc-driven apoptosis via PIK3CA/Akt/mTOR and COX-2 in a mouse model of human liver cancer. , 2008, Gastroenterology.

[71]  O. Perez,et al.  Genomic and proteomic analysis reveals a threshold level of MYC required for tumor maintenance. , 2008, Cancer research.

[72]  Kathryn A. O’Donnell,et al.  c-Myc-regulated microRNAs modulate E2F1 expression , 2005, Nature.

[73]  M. Buendia,et al.  The hepatitis B virus X gene potentiates c-myc-induced liver oncogenesis in transgenic mice , 1997, Oncogene.

[74]  Jennifer A. Smith,et al.  The Brd4 Extraterminal Domain Confers Transcription Activation Independent of pTEFb by Recruiting Multiple Proteins, Including NSD3 , 2011, Molecular and Cellular Biology.

[75]  S. Thorgeirsson,et al.  Molecular analyses of liver tumors in c-myc transgenic mice and c-myc and TGF-alpha double transgenic mice. , 1996, Cancer Letters.

[76]  Masaomi Kato,et al.  microRNAs: small molecules with big roles –C. elegans to human cancer , 2008, Biology of the cell.

[77]  Tsung-Cheng Chang,et al.  Widespread microRNA repression by Myc contributes to tumorigenesis , 2008, Nature Genetics.

[78]  P. Gallant,et al.  Max-independent functions of Myc in Drosophila melanogaster , 2008, Nature Genetics.

[79]  A. Sumberaz,et al.  Human carcinogenesis and alcohol in hepato-gastroenterology. , 2012, European review for medical and pharmacological sciences.

[80]  M. Strauss,et al.  Lack of p53 accelerates hepatocarcinogenesis in transgenic mice constitutively overexpressing c‐myc in the liver , 2001, FASEB journal : official publication of the Federation of American Societies for Experimental Biology.

[81]  Bruno Amati,et al.  Oncogenic activity of the c-Myc protein requires dimerization with Max , 1993, Cell.

[82]  R. Young,et al.  BET Bromodomain Inhibition as a Therapeutic Strategy to Target c-Myc , 2011, Cell.

[83]  S. Schreiber,et al.  Signaling Network Model of Chromatin , 2002, Cell.

[84]  X. Wang,et al.  Stem cell-like micro-RNA signature driven by Myc in aggressive liver cancer , 2010, Proceedings of the National Academy of Sciences.

[85]  C. Day,et al.  Genetic predisposition to alcoholic liver disease. , 1992, Gut.

[86]  P. Vogt,et al.  Avian acute leukemia viruses MC29 and MH2 share specific RNA sequences: evidence for a second class of transforming genes. , 1979, Proceedings of the National Academy of Sciences of the United States of America.

[87]  S. Ahn,et al.  Development of a transgenic mouse model of hepatocellular carcinoma with a liver fibrosis background , 2016, BMC Gastroenterology.

[88]  E. Prochownik c-Myc: linking transformation and genomic instability. , 2008, Current molecular medicine.

[89]  S. Cairo,et al.  Myc target miRs and liver cancer: small molecules to get Myc sick. , 2012, Gastroenterology.

[90]  R. Eisenman,et al.  Myc and Max proteins possess distinct transcriptional activities , 1992, Nature.

[91]  C. Dang,et al.  Max: functional domains and interaction with c-Myc. , 1992, Genes & development.

[92]  D. Felsher,et al.  Inactivation of MYC reverses tumorigenesis , 2014, Journal of internal medicine.

[93]  M. Avila,et al.  New molecular interactions of c‐Myc in cholangiocarcinoma may open new therapeutic opportunities , 2016, Hepatology.

[94]  R. Brůha,et al.  Alcoholic liver disease. , 2012, World journal of hepatology.

[95]  G. Wahl,et al.  c-Myc can induce DNA damage, increase reactive oxygen species, and mitigate p53 function: a mechanism for oncogene-induced genetic instability. , 2002, Molecular cell.

[96]  H. El‐Serag Hepatocellular carcinoma and hepatitis C in the United States , 2002, Hepatology.

[97]  C. Martínez-A,et al.  c-Myc regulates cell size and ploidy but is not essential for postnatal proliferation in liver. , 2005, Proceedings of the National Academy of Sciences of the United States of America.

[98]  Kathryn A. O’Donnell,et al.  Therapeutic microRNA Delivery Suppresses Tumorigenesis in a Murine Liver Cancer Model , 2009, Cell.

[99]  M. Muroni,et al.  Down-regulation of c-myc and Cyclin D1 genes by antisense oligodeoxy nucleotides inhibits the expression of E2F1 and in vitro growth of HepG2 and Morris 5123 liver cancer cells. , 2003, Carcinogenesis.

[100]  P. Leder,et al.  Translocation of the c-myc gene into the immunoglobulin heavy chain locus in human Burkitt lymphoma and murine plasmacytoma cells. , 1982, Proceedings of the National Academy of Sciences of the United States of America.

[101]  R. Eisenman,et al.  Max: a helix-loop-helix zipper protein that forms a sequence-specific DNA-binding complex with Myc. , 1991, Science.

[102]  J. Ward,et al.  Role of Myc in hepatocellular proliferation and hepatocarcinogenesis. , 2014, Journal of hepatology.

[103]  M. Lai,et al.  Genome of avian myelocytomatosis virus MC29: analysis by heteroduplex mapping. , 1979, Proceedings of the National Academy of Sciences of the United States of America.

[104]  R. Bataller,et al.  Alcoholic liver disease: pathogenesis and new therapeutic targets. , 2011, Gastroenterology.

[105]  M. Rattray,et al.  A tumor progression model for hepatocellular carcinoma: bioinformatic analysis of genomic data. , 2006, Gastroenterology.

[106]  J. Chow,et al.  Small-molecule c-Myc inhibitor, 10058-F4, inhibits proliferation, downregulates human telomerase reverse transcriptase and enhances chemosensitivity in human hepatocellular carcinoma cells , 2007, Anti-cancer drugs.

[107]  Vijay Kumar,et al.  Specific inhibition of gene expression and transactivation functions of hepatitis B virus X protein and c‐myc by small interfering RNAs , 2004, FEBS letters.

[108]  L. Roberts,et al.  Myc, Max, and Mnt: molecular mechanisms of enhancement of cholangiocarcinogenesis by cholestasis. , 2011, Gastroenterology.

[109]  M. Perricaudet,et al.  Full-length and truncated versions of the hepatitis B virus (HBV) X protein (pX) transactivate the cmyc protooncogene at the transcriptional level. , 1991, Biochemical and biophysical research communications.

[110]  F. Bosch,et al.  Overexpression of c-myc in diabetic mice restores altered expression of the transcription factor genes that regulate liver metabolism. , 2002, The Biochemical journal.

[111]  S. Lee,et al.  Hepatitis B virus X protein enhances Myc stability by inhibiting SCFSkp2 ubiquitin E3 ligase-mediated Myc ubiquitination and contributes to oncogenesis , 2016, Oncogene.

[112]  Dean W. Felsher,et al.  Cellular senescence is an important mechanism of tumor regression upon c-Myc inactivation , 2007, Proceedings of the National Academy of Sciences.

[113]  S. Thorgeirsson,et al.  MYC activates stem-like cell potential in hepatocarcinoma by a p53-dependent mechanism. , 2014, Cancer research.

[114]  Chien-Ru Liu,et al.  Targeting c-Myc as a novel approach for hepatocellular carcinoma. , 2010, World journal of hepatology.

[115]  F. Heindryckx,et al.  Experimental mouse models for hepatocellular carcinoma research , 2009, International journal of experimental pathology.

[116]  Yu Wei,et al.  Hepatic stem-like phenotype and interplay of Wnt/beta-catenin and Myc signaling in aggressive childhood liver cancer. , 2008, Cancer cell.

[117]  J F Barrett,et al.  Identification of CDK4 as a target of c-MYC. , 2000, Proceedings of the National Academy of Sciences of the United States of America.

[118]  Y. Morishita,et al.  Amplification of c-myc in Hepatocellular Carcinoma: Correlation with Clinicopathologic Features, Proliferative Activity and p53 Overexpression , 1999, Oncology.

[119]  S. Thorgeirsson,et al.  Application of comparative functional genomics to identify best-fit mouse models to study human cancer , 2004, Nature Genetics.

[120]  F. Bosch,et al.  Prevention of diabetic alterations in transgenic mice overexpressing Myc in the liver. , 1996, Proceedings of the National Academy of Sciences of the United States of America.

[121]  Kathryn A. O’Donnell,et al.  Hepatoblastoma modeling in mice places Nrf2 within a cancer field established by mutant β-catenin. , 2016, JCI insight.

[122]  T. Copetti,et al.  Anticancer Targets in the Glycolytic Metabolism of Tumors: A Comprehensive Review , 2011, Front. Pharmacol..

[123]  F. Tacke,et al.  Enhanced expression of c-myc in hepatocytes promotes initiation and progression of alcoholic liver disease. , 2015, Journal of hepatology.

[124]  L. Zender,et al.  A MYC–aurora kinase A protein complex represents an actionable drug target in p53-altered liver cancer , 2016, Nature Medicine.

[125]  J. Bishop,et al.  DNA and RNA from Uninfected Vertebrate Cells Contain Nucleotide Sequences Related to the Putative Transforming Gene of Avian Myelocytomatosis Virus , 1979, Journal of virology.

[126]  H. Hermeking,et al.  Mediation of c-Myc-induced apoptosis by p53. , 1994, Science.

[127]  R. Cardiff,et al.  c-MYC induces mammary tumorigenesis by means of a preferred pathway involving spontaneous Kras2 mutations , 2001, Nature Medicine.

[128]  J. Bartek,et al.  E2F activity is essential for survival of Myc-overexpressing human cancer cells , 2002, Oncogene.

[129]  J. Bishop Retroviruses and cancer genes. , 1982, Advances in cancer research.

[130]  Chi V. Dang,et al.  c-Myc Target Genes Involved in Cell Growth, Apoptosis, and Metabolism , 1999, Molecular and Cellular Biology.

[131]  S. Thorgeirsson,et al.  Coexpression of C‐myc and transforming growth factor alfa in the liver promotes early replicative senescence and diminishes regenerative capacity after partial hepatectomy in transgenic mice , 1997, Hepatology.

[132]  Shuhan Sun,et al.  Characterization of the genotype and integration patterns of hepatitis B virus in early‐ and late‐onset hepatocellular carcinoma , 2015, Hepatology.

[133]  M. Vasseur-Cognet,et al.  Glucose Regulation of Gene Transcription* , 2000, The Journal of Biological Chemistry.

[134]  Vijay Kumar,et al.  Antisense regulation of expression and transactivation functions of the tumorigenic HBx and c-myc genes. , 2006, Biochemical and biophysical research communications.